There are four naturally occurring tocotrienols, d-alpha-, d-beta-, d-gamma-, and d-delta-tocotrienol. The four naturally occurring tocotrienols have the (R) absolute configuration at the C-2 chroman ring position, and the chemical structures wherein R1 (at C-5 chroman ring position), R2 (at C-7 chroman ring position), and R3 (at C-8 chroman ring position) are methyl in the d-alpha- homologue, R1 and R3 are methyl in the d-beta-homologue, R2 and R3 are methyl in the d-gamma- homologue, and R3 is methyl in the d-delta homologue, with the non-methyl R groups being hydrogen atoms.

The chroman ring numbering system referenced above is used herein for continuity. As shown, each of the four naturally occurring d-tocotrienols has an (R) absolute configuration at the chiral 2-position carbon of the chroman ring. Further, the tocotrienols have a trans double bond site at each of the 3′ and 7′ chain positions in the 16-carbon side chain attached to the chroman ring. The geometry of each of these double bond sites is trans (also referred to as E) in all four natural tocotrienols.
For a general discussion of the natural tocotrienols, see L. Machlin, ed., “Vitamin E: A Comprehensive Treatise”, Dekker, N.Y., 1980, pp. 8–65.
The family of d-tocotrienols has been shown to possess a wide variety of health benefits. For a discussion of the health-promoting benefits of tocotrienols, see T. R. Watkins, et al., “Tocotrienols: Biological and Health Effects”, K. L. Jordan Heart Foundation, Montclair, N.J., 1999; C. Chenevert and G. Courchesne, “Synthesis of (S)-alpha-Tocotrienol via an enzymatic desymmetrization of an achiral chroman derivative”, Tetrahedron Letters 43, 7971–7973 (2002); and B. C. Pearce et al., “Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols”, J. Med. Chem. 35, 3595–3606 (1992).
d-Tocotrienols are present in the oils, seeds, and other parts of many plants used as foods (see pp. 99–165 in L. Machlin, ed., “Vitamin E: A Comprehensive Treatise” for a discussion of the occurrence of tocotrienols in foods). However, since d-tocotrienol levels are very low in these natural sources it is often necessary to supplement the typical human diet with additional tocotrienols in order to realize the potential health advantages provided by these compounds. Tocotrienol-containing concentrates can be prepared from certain plant oils and plant oil by-products such as rice bran oil or palm oil deodorizer distillate. For examples of such isolation processes, see for instance A. G. Top et al., U.S. Pat. No. 5,190,618 (1993) or Y. Tanaka and T. Ichitani, Jpn. Kokai Tokkyo Koho appl. JP 2002-168227 20020610 (2003), CAN 139:52035.
There are two problems inherent in obtaining d-tocotrienols from natural sources. Firstly, there is only a limited and inadequate supply of the requisite plant or seed oils available for use as tocotrienol feedstocks. Secondly, the d-tocotrienol yield from such processes is a mixture of varying amounts of all of the natural tocols. In order to obtain a pure member of the d-tocotrienol family, it has been necessary to resort to very expensive procedures such as preparative scale reversed-phase chromatography or simulated moving bed chromatography. For an example of such a purification process, see M. Kitano et al., Japanese Patent No. 200302777 (2003), CAN 133:309299.
In view of the limited availability and difficulty of isolation of natural d-tocotrienols, it is necessary to seek ways for obtaining the materials through chemical synthesis from commercially available raw materials. The synthesis of tocotrienols in the natural d- form, having the (2R) chiral configuration and trans double bonding at the proper locations in the side chain, has heretofore proven to be of considerable difficulty.
The first attempt to synthesize a member of the tocotrienol family was reported by P. Karrer and H. Rentschler (Helv. Chim. Acta 27, 1297–1300 (1944)); these workers failed to synthesize tocotrienols. Karrer and Rentschler obtained compounds having cyclization of the side chain. A later attempt by D. McHale et al. (J. Chem. Soc. 1963, 784–791) likewise failed due to inadvertant cyclization of the olefin-containing side chain.
Syntheses of various members of the tocotrienol family in the d,l- or (RS)-form have been published. Schudel et al. (Helv. Chim. Acta 46, 2517–2526 (1963)) completed a synthesis of alpha- and delta-tocotrienols in racemic form (dl-alpha- and delta-tocotrienols, each having a 50/50 mixture of R- and S-enantiomers at the 2-position). Schudel's synthesis was not amenable to synthesis of the natural 2R-isomer. Other tocotrienol syntheses include the works reported by H. Mayer et al., Helv. Chim. Acta 50, 1376–11393 (1967); H.-J. Kabbe and H. Heitzer, Synthesis 1978, 888–889; M. Kajiwara et al., Heterocycles 14, 1995–1998 (1980); S. Urano et al., Chem. Pharm. Bull. 31, 4341–4345 (1983), Pearce et al., J. Med Chem. 35, 3595–3606 (1992), and Pearce et al., J. Med. Chem. 37, 526–541 (1994). As in the case of Schudel et al., none of these reported processes lead to the natural d-form of the tocotrienols, but rather produces racemic mixtures.
Several syntheses of natural form d-tocotrienols have been published. J. Scott et al., Helv. Chim. Acta 59, 290–306 (1976), started with trimethyl-hydroquinone and used a conventional optical resolution to provide the key intermediate 2,5,7,8-tetramethyl-6-hydroxychroman-2-acetic acid in the natural enantiomeric form. This compound was then elaborated into d-alpha-tocotrienol by a thrice-iterated process of adding 5-carbon sections of the side chain at a time, as follows:
Unfortunately this synthesis produced d-alpha-tocotrienol contaminated with about 20% of the isomeric compound shown. The authors were unable to separate pure natural-form tocotrienol from this mixture.
Sato et al. (Japanese Patent 63063674 A2 19880322 Showa; CAN 110:193145) described an approach to d-alpha-tocotrienol in which the diterpene alcohol geranylgeraniol is converted to an epoxytriene through Sharpless asymmetric epoxidation. The epoxidation is elaborated through several steps into the chiral acetoxy sulfide shown below. This C20 chain is then attached to a suitably protected trimethylhydroquinone to provide the illustrated open-chain sulfide. The sulfide was subsequently desulfurized, the acetates removed, and cyclized to form a chiral chroman, as shown:
While the above synthesis produces natural-equivalent d-alpha-tocotrienol, it suffers from the fact that the geranylgeraniol starting material is very difficult to obtain.
In an apparent effort to overcome this difficulty, Sato et al. (JP 01233278 A2 19890919 Heisei, 1989; CAN 112:139621) report a second synthesis of d-alpha-tocotrienol which replaces the use of geranylgeraniol with a much more readily available side-chain synthon, the p-tolylsulfone derived from the readily available C10 terpene alcohol, geraniol. This synthesis, outlined below, requires an unsuitably large number of steps for commercial use.

In other relevant syntheses, Scott et al. prepared a chiral C15 chroman and added 5-carbon chains to it three times to make the final product tocotrienol. Sato used a C9 hydroquinone and a C20 chain derived from geranylgeraniol. Sato used an intermediate C18 chroman section and a C10 geranyl section.
In the only reported synthesis in the tocotrienol area that is truly highly convergent, Chenevert and Courchesne (Tetrahedron Letters 43, 7971–7973 (2002)) formed unnatural (S) or (l)-alpha-tocotrienol in a process starting with the achiral triol, dl-chromantriol. As shown in the process illustrated below, Chenevert and Courchesne first converted the achiral triol to a (S) monoester via enzymatic desymmetrization and acetylation. Then, the (S) monoester was further treated with two equivalents of mesyl chloride to provide a (R) dimesylated monoester chroman. Reduction of the dimesylated monoester chroman produced (R)-chromanol, a chroman substituted with a hydroxymethyl group at the 2-position and a hydroxyl group at the 6-position of the chroman ring, and having (R) absolute configuration at the chiral 2-position carbon. Unnatural (S) or (l)-alpha-tocotrienol was thereafter produced from the 14-carbon (R)-chromanol compound via substituting the hydroxyl group at the 6-position with a benzyl ester protecting group, substituting the hydroxyl portion of the 2-hydroxymethyl group with a triflate (—OSO2CF3) leaving group to form a triflated chroman protected at the 6-position. The triflated chroman was thereafter coupled with phenyl farnesyl sulfone, i.e., a 15-carbon branched carbon chain having three methylated trans double bond sites corresponding to the 16-carbon side chain of a tocopherol, less the methyl carbon attached to the 2-position carbon of the chroman ring. As generation of the carbanion from the sulfone allowed for farnesyl group alkyl substitution of the triflate leaving group on the chroman ring, alpha-tocotrienol retaining the unnatural (S) or (l) configuration at the chiral chroman carbon is produced. The process is illustrated below:
The use of the achiral chroman triol as starting material in the (l)-alpha-tocotrienol synthesis of Chenevert and Courchesne does not show any advantages in either yield, number of steps, or economic advantage over previously reported chemistry that has suffered from being unattractive in each of these aspects. Moreover, the tocotrienol produced thereby is in the unnatural, and far less useful, (l) enantiomeric form.
In light of the above, there remains a need for commercially suitable processes of synthesizing members of the naturally occurring d-tocotrienol family using commercially available starting materials and requiring a number of steps that is economically feasible on a commercial scale. New routes for producing heretofore relatively unavailable starting materials for such synthesis would be valuable. In particular, there is a need for a more economically acceptable starting materials and syntheses for making each of d-beta, d-gamma, and d-delta tocotrienols.